The immune system consists of two branches, that while separated by speed and specificity, are intricately linked, creating a rapid and directed response against both endogenous and exogenous insults16,21. The innate immune system provides immediate host defense against physical, chemical and microbiological insults16,21. It involves neutrophils, monocytes, macrophages, complement, cytokines and acute phase proteins16,21. Despite the lack of antigen specificity, the innate immune system is able to recognize self from non-self, foreign peptides16,21. Adaptive immunity, however, involves B- and T-lymphocytes in a highly specific antigen directed response16,21. One advantage of adaptive immunity is the potential for immune memory, leading to stronger and more rapid response on further stimulation8,9.
The defining feature of adaptive immunity (specific immunity) is the use of T and B-lymphocytes bearing antigen-specific receptors in a targeted immune response16,21. The major T-cell effectors are the T-helper cells, bearing CD4 receptors and cytotoxic T-cells bearing CD8 receptors16,21. T-helper cells interact with MHC II, and are responsible for coordinating the immune response, recognizing foreign antigens, activating various parts of the immune system and activating B-cells. Cytotoxic T-cells interact with MHC I receptors and play a role in mounting an immune response against exogenous pathogens16,21.
The Major Histocompatibility Complex (MHC) is a genetic region that codes for proteins that play an essential role in regulating and modulating immune response10,16. The gene products of the MHC are divided into two separate groups, based on structure and biological properties: MHC II and MHC II10,16. MHC class I receptors are present on all nucleated cells10,16. They present endogenously-synthesized peptides and are intimately involved in self-self recognition. MHC class II receptors are only found on cells involved with immune responses and present exogenously-derived proteins such as those from bacterial production10,16. Classically, MHC I was thought to be involved in tumour rejection, but more recently MHC II has been found to play a role.
The diversity of antigen binding by MHC class I molecules is based on three basic and interrelated principles. First, class I molecules have the ability to bind peptides with many different sequences2,16. These MHC class 1: antigen complexes can be recognized by the cytotoxic T-lymphocytes (CDS), eventually leading to the destruction of any cell carrying a similar foreign protein2,16. Secondly, each organism expresses a number of different class I genes2,16. Lastly, MHC exhibits polymorphisms with a number of alleles at each locus2,16,23. In humans, the MHC I is represented at more than one locus called the Human Leukocyte Antigen (HLA), the loci being HLA-A,-B and -C, the most polymorphic of which is HLA-B16,23. These factors imply a high degree of individual specificity and the need for a regulator to exert selective pressure: the cellular immune system.
It is this high degree of specificity and overriding selective pressure that is exploited in the transplantation of organs and tissues between individuals23. Identical twins and genetically close family members are less likely to reject transplanted tissue since they have similar HLA loci16. This is based on the fact that the MHC I are expressed co-dominantly and in most cases inherited intact without recombination16,23. Therefore, homozygous individuals such as identical twins and syngeneic rats could theoretically accept a brain tumour from his/her homozygous donor. Yet more critically, they would reject a brain tumour from a heterozygous donor based on a specific and targeted immune response.
As stated earlier, MHC class I receptors are surface glycoproteins located on most cells that play a crucial role in immune response, These MHC class I bind to antigenic peptides and interact with NK cells and CD85,16,25. These peptides are derived from degraded endogenous proteins from virus and tumour infected cells5,16,25. Antigen processing is a complex mechanism that involves numerous steps. A defect in any of these steps may lead to non-expression of the MHC class I: antigen complex, and escape from T-cell recognition and destruction12. The loss of or dysregulation on MHC I complexes is a frequent mechanism for evading destruction from CD812. Intuitively, one might assume that this “missing self”17 marker might lead to increased recognition by NK cells, which are inhibited by interacting with the MHC I complex, and stimulated by cells with down-regulated HLA-2/HA expression18. Yet even with a fully functioning immune system, it is possible for tumours to evade recognition through the use of an elusive escape strategy12. Although the mechanism of escape is poorly understood, experiments have described several mechanisms allowing tumours to escape recognition by the immune system. These mechanisms range from loss or mutation of HLA halotypes to unresponsiveness to interferons12. So while a change of or loss of MHC class I receptors is associated with the genesis of various tumours, the presence of MHC class I molecules has been shown to participate in cancer resistance.
An example of the anti-tumourogenic effects of MHC class I molecule is in the immune surveillance of mitochondrial DNA integrity. In one study, one of the roles of MHC I molecules was to eliminate cells carrying mitochondrial mutation13. Human glioma cells carry multiple mutations in both the mitochondrial DNA and in the mitochondrial complex7. From this data, it is possible to assume that gliomas of the same histological type/grade will carry similar mutations in their DNA and have similar abnormal surface proteins associated with both MHC class I molecules and the cell membrane. Conversely, an intact immune system can also allow for the development and progression of tumours.
It has been shown that the progression of certain cancers is associated with the expression of tumour-specific antigens and an associated immune response15. Therefore, effective tumour rejection and immunity cannot be achieved solely by self-vaccination. Despite these barriers, there is increasing evidence that the immune system can be used to combat cancer. While both a dysregulated and normally functioning immune system fight against immune rejection of cancer, there have been reported results of the spontaneous rejection of malignant tumoure19,26. Interestingly, it has also been suggested that autoimmune diseases may contribute to a better prognosis in patients with malignant tumours6,19. In these patients, the majority of the IgG specificities identified share considerable homology with both human and microbial peptides14. This has lead to the hypothesis that molecular mimicry may initiate the observed tumour autoimmunity. Studies related to this have shown long term remission of malignant brain tumours after intracranial infection in four patients4, and improved survival of cancer patients with microbial infection20,22. This brings into question whether the molecular mimicry induced autoimmunity can be used to treat tumours. Importantly, significant homology has been shown to exist between human proteins and proteins from other species24. Further experiments have shown that xenogeneic antigen from endothelial cells can break immune tolerance against autologous angiogeneic endothelial cells20. This suggests that self-tolerance to tumours may be broken through cross-reactivity with a homologous foreign antigen